The present invention relates to anticancer platinum(IV) complexes for oral administration and a preparation method thereof. More particularly, the present invention relates to lipophilic platinum(IV) complexes. which are potent anticancer agents when administered orally, represented by Formula I and a preparation method thereof. ##STR2## (wherein A--A is a symmetric diamine that can chelate to platinum and is selected from the group consisting of ethylene diamine (NH.sub.2 CH.sub.2 CH.sub.2 NH.sub.2), t(.+-.)-1,2-diaminocyclohexane ##STR3## 2,2-dimethyl-1,3-propanediamine (NH.sub.2 CH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 NH.sub.2), cyclohexane-1.1-dimethanamine ##STR4## and tetrahydro-4H-pyran-4.4-dimethanamine (O(CH.sub.2 CH.sub.2).sub.2 C(CH.sub.2 NH.sub.2).sub.2), and an anionic group R is selected from the group consisting of propionyl (C.sub.2 H.sub.5 CO), butyryl (C.sub.3 H.sub.7 CO) and valeryl (C.sub.4 H.sub.9 CO) groups.
The present inventors have found that the platinum(IV) complexes which contain one of the symmetric diamines above and four identical carboxylic groups can be easily absorbed in the gastrointestinal track due to their high lipophilicity, and thus are potent oral anticancer drugs. The only two platinum complexes that are currently in clinical use are cisplatin (cis-(NH.sub.3).sub.2 PtCl.sub.2), and carboplatin ##STR5## These platinum complexes are administered via injection, and orally administrable anticancer drugs have not yet been developed. Moreover, despite the high anticancer activity of these platinum (II) complexes for injection, their use is limited due to their severe side effects, such as nephrotoxicity and neurotoxicity (F. K. V. Leh, et. al, J. Pharm. Sciences, 65, 315 (1976)). Furthermore, these platinum (II) complexes for injection exhibit narrow therapeutic spectrum and cross-resistance. Therefore, a great deal of efforts have been made to develop the third generation anticancer drug for oral administration which show a wider therapeutic specturm and no cross-resistance. To date, however, such efforts have not been successful. Recently, researches are actively underway to find orally active platinum(IV) anticancer drugs. The oral route is preferred to injection since not only oral administration is presumed to reduce the side effects due to cytotoxicity resulting from injection of the drug, but also, it is more convenient and cost-effective for patients since they do not have to be hospitalized for treatment. Despite the need for such oral anticancer drugs, development has not been successful because some strict requirements should be satisfied. First of all, the oral anticancer drug must be chemically stable in the highly acidic (pH=1-2) environment of the stomach, and secondly, it must be well absorbed in the gastro-intestinal track. Most of the 4-coordinate platinum (II) complexes do not satisfy these requirements, and only 6-coordinate platinum(IV) complexes can be considered as a possible oral anticancer agent (C. M. Giadomenico et.al., Inorg. Chem. 34, 1015 (1995)). Thirdly, the oral platinum (IV) anticancer drugs must have an appropriate reduction properties since they need to be reduced to a platinum (II) complex to combine with deoxyribonucleic acid (DNA) in the cell (L. T. Ellis et. al., Aust. J. Chem. 48 793 (1995)). Therefore, despite the efforts, the 6-coordinate platinum (IV) complex anticancer agents have not been commercialized to date. Only JM216 (cis, trans, ##STR6## (M. Abrams, European patent pending 89300787.2) developed by Johnson-Matthey of Great Britain is in the clinical phase II study and Cn-OHP (cis, trans, ##STR7## (Y. Kidany, European patent pending 94202874.7) of the Kidany's group in Japan is in preparation for clinical studies.
The conventional method for preparation of preparing the 6-coodinate platinum(IV) complexes is to first synthesize 4-coordinate platinum(II) complexes which are expected to have anticancer activity, and oxidize them by using hydrogen peroxide or halogens. Then the newly added axial ligands, that is hydroxyl or halide (such as chloride and bromide) groups are substituted with a different ligand such as carboxylate groups (C. M. Giandomenico et. al., Inorg. Chem. 34, 1015 (1995)). Such conventional oxidative addition reaction for the 6-coordinate platinum(IV) complexes can afford only variation of the axial ligands. And moreover, such nucleophilic substitution is known to be very difficult because of the intrinsic inertness of metal-ligand bonds in the octahedral platinum(IV) complexes (M. Galanski et. al., Inorg. Chem. 1996, 35, 1709).